Application of toxicogenomic profiling to evaluate effects of benzene and formaldehyde: from yeast to human.

Genetic variation underlies a significant proportion of the individual variation in human susceptibility to toxicants. The primary current approaches to identify gene-environment (GxE) associations, genome-wide association studies and candidate gene association studies, require large exposed and control populations and an understanding of toxicity genes and pathways, respectively. This limits their application in the study of GxE associations for the leukemogens benzene and formaldehyde, whose toxicity has long been a focus of our research. As an alternative approach, our published work has applied innovative in vitro functional genomics testing systems, including unbiased functional screening assays in yeast and a near-haploid human bone marrow cell line. Through comparative genomic and computational analyses of the resulting data, human genes and pathways that may modulate susceptibility to benzene and formaldehyde were identified, and the roles of several genes in mammalian cell models were validated. In populations occupationally exposed to low levels of benzene, we applied peripheral blood mononuclear cell transcriptomics and chromosome-wide aneuploidy studies in lymphocytes. In this review, we describe our comprehensive toxicogenomic approach and the potential mechanisms of toxicity and susceptibility genes identified for benzene and formaldehyde, as well as related studies conducted by other researchers.